While there are numerous compositions and methods known in the art to treat pain and inflammation, numerous difficulties remain. Most significantly, side effects over long administration periods and/or higher dosages often limit the use of such drugs. For example, certain COX-2 inhibitors are implicated in adverse cardiovascular events and aspirin-type pain medication often increase the risk of intestinal bleeding. In other examples, ibuprofen and acetaminophen tend to negatively impact hepatic function, especially at higher dosages.
Ethanolamides of long-chain fatty acids, usually referred to as N-acylethanolamines (NAEs), are present in numerous lower and higher organisms, and mammals with a wide variety of functions. For example, anandamide, a polyunsaturated fatty acid-type NAE, was demonstrated to have cannabimimetic activity. In contrast, saturated and monounsaturated NAEs are inactive as ligands of cannabinoid receptors. However, such compounds have been reported to possess a variety of other biological activities. For example, N-oleoylethanolamine, a monounsaturated fatty acid-type NAE, was shown to be anorexic via the peroxisome proliferator-activated receptor-α (PPAR-α), and N-stearoylethanolamine, a saturated fatty acid-type NAE, to be pro-apoptotic and anorexic.
N-palmitoylethanolamine (PEA), the naturally occurring amide of palmitic acid and ethanolamine, is a member of the saturated fatty acid-type NAE family. PEA has been shown to inhibit peripheral inflammation and mast cell degranulation (Mazzari et al., European Journal of Pharmacology 1996, 300, 227-36; Berdishev et al., Life Science 1998, 63, 125-129; D'Agostino et al., Journal of Pharmacology and Experimental Therapeutics 2007, 322, 1137-1143), as well as to exert antinociceptive effects in rats and mice (Calignano et al., Nature 1998, 394, 277-281; Calignano et al., European Journal of Pharmacology 2001, 419, 191-198).
These properties have been shown to be dependent on PPAR-α, and PEA activates this nuclear receptor with a potency comparable to the synthetic agonist WY14,643 (Lo Verme et al., Molecular Pharmacology 2005, 67, 15-19; Lo Verme et al., Journal of Pharmacology and Experimental Therapeutics 2006, 319, 1051-1061).
In the carrageenan-induced paw edema and phorbol ester-induced ear edema models, PEA applied as a drug attenuates inflammation in wild-type mice, but has no effect in mice lacking PPAR-α (see LoVerme et al., Molecular Pharmacology 2005, 67, 15-19). PEA was also found to suppress pain behaviors induced, in mice, by chemical tissue injury, nerve damage, or inflammation (see LoVerme et al., Journal of Pharmacology and Experimental Therapeutics 2006, 319, 1051-1061).
In addition to the pharmacological activities shown in animal models, PEA has been reported to attenuate skin inflammation in humans (Kemeny et al., Skin Pharmacology and Physiology 2007, 20, 155-161).
Activation of PPAR-α by selective receptor agonists could be envisaged as a viable approach for the treatment of inflammatory and pain states. However, the prolonged clinical use of PPAR-α agonists has been linked to serious adverse events, which include oncogenesis, renal dysfunction, and cardiovascular toxicity (Nissen et al., JAMA 2007, 297, 1362-1373). Sustaining PEA signaling at PPAR-α by protecting this lipid amide from degradation is envisaged as an alternative to direct PPAR-α activation by receptor agonists.
NAEs are substrate of the N-acylethanolamine acid amidase (NAAA), an enzyme that catalytically hydrolyzes the NAE to ethanolamine and the corresponding fatty acid. NAAA is a cysteine hydrolase that belongs to the N-terminal nucleophile (Ntn) family of enzymes (Tsuboi et al., Journal of Biological Chemistry 2005, 280, 11082-11092; Tsuboi et al., Chemistry and Biodiversity 2007, 4, 1914-1925). NAAA exhibits a substantial preference for PEA over other NAEs. Therefore, inhibition of NAAA is expected to decrease the inactivation and restore the levels of PEA in pathological conditions characterized by markedly reduced concentrations of this signaling molecule.
There exists a problem in the field to which the instant invention pertains related to the preparation of new inhibitors of NAAA for use in the preparation of pharmaceutical composition therapeutics. Surprisingly, the instant invention solves this as well as several other problems in the relevant field by providing, inter alia, small molecule chemical inhibitors of NAAA as well as methods for treating pain and inflammation.